Investigations into inhibition and regulation of cholesterol biosynthesis will be conducted based on the discovery that 4,4,108-trimethyl-trans-decal-3 beta-ol (TMD) and related compounds are structurally novel, efficient and specific inhibitors of cholesterol biosynthesis at the squalene oxide cyclization stage. The proposed investigations will involve experiments in rat liver homogenates, in tissue culture cells, and, collaboratively, in perfused liver and intact rat. The mechanism of inhibition by TMD and related compounds will be studied further by, for example, synthesis and testing of compounds designed to elucidate the minimum structural requirements for inhibition. The possibility that squalene dioxide, which accumulates when TMD is used to inhibit squalene oxide cyclase, has a role in cholesterol regulation either itself or through its conversion to dioxygenated sterol precursors and 25-hydroxycholesterol will be investigated. The proposed research offers promise in helping to combat atherosclerosis both through its contribution to a fundamental understanding of cholesterol regulation and through the possibility of development of useful anticholesterolemic agents.